The histone variant H2A.Z (Htz1p) has been implicated in transcriptional regulation in numerous organisms, including Saccharomyces cerevisiae. Genome-wide transcriptome profiling and chromatin immunoprecipitation studies identified a role for Htz1p in the rapid and robust activation of many oleate-responsive genes encoding peroxisomal proteins, in particular POT1, POX1, FOX2, and CTA1. The Swr1p-, Gcn5p-, and Chz1p-dependent association of Htz1p with these promoters in their repressed states appears to establish an epigenetic marker for the rapid and strong expression of these highly inducible promoters. Isw2p also plays a role in establishing the nucleosome state of these promoters and associates stably in the absence of Htz1p. An analysis of the nucleosome dynamics and Htz1p association with these promoters suggests a complex mechanism in which Htz1p-containing nucleosomes at fatty acid-responsive promoters are disassembled upon initial exposure to oleic acid leading to the loss of Htz1p from the promoter. These nucleosomes reassemble at later stages of gene expression. While these new nucleosomes do not incorporate Htz1p, the initial presence of Htz1p appears to mark the promoter for sustained gene expression and the recruitment of TATA-binding protein.
Tissue plasminogen activator (tPA) is overexpressed in pancreatic ductal carcinoma and is involved in tumor progression. This effect is probably mediated through the activation of angiogenesis, cell invasion, and cell proliferation. Previous studies support the notion that the effects of tPA on cell invasion require its proteolytic activity. Here, we report the molecular mechanism responsible for the proliferative effects of tPA on pancreatic tumor cells. tPA activates the extracellular signal-regulated kinase 1/2 signaling pathway in a manner that is independent of its catalytic activity. We also show that at least two membrane receptors, epidermal growth factor receptor and annexin A2, which are overexpressed in pancreatic cancer, are involved in the transduction of tPA signaling in pancreatic tumors. This observation suggests the establishment of an amplification loop in tumor cell proliferation. Double immunofluorescence experiments showed co-localization of tPA/epidermal growth factor receptor and tPA/annexin A2 in pancreas cancer cells. These results add novel insights into the non-catalytic functions of tPA in cancer and the molecular mechanisms behind the effects of this protease on cell proliferation, including a role for epidermal growth factor receptor. (Am J Pathol 2007, 170
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